Modifying Phosphate Toxicity in Chronic Kidney Disease

Abstract

Phosphate toxicity is a well-established phenomenon, especially in chronic kidney disease (CKD), where hyperphosphatemia is a frequent occurrence when CKD is advanced. Many therapeutic efforts are targeted at phosphate, and comprise dietary intervention, modifying dialysis schemes, treating uncontrolled hyperparathyroidism and importantly, phosphate binder therapy. Despite all these interventions, hyperphosphatemia persists in many, and its pathological influence is ongoing. In nephrological care, a somewhat neglected aspect of treatment-when attempts fail to lower exposure to a toxin like phosphate-is to explore the possibility of "anti-dotes". Indeed, quite a long list of factors modify, or are mediators of phosphate toxicity. Addressing these, especially when phosphate itself cannot be sufficiently controlled, may provide additional protection. In this narrative overview, several factors are discussed that may qualify as either such a modifier or mediator, that can be influenced by other means than simply lowering phosphate exposure. A wider scope when targeting phosphate-induced comorbidity in CKD, in particular cardiovascular disease, may alleviate the burden of disease that is the consequence of this potentially toxic mineral in CKD.

Keywords: CKD-MBD; chronic kidney disease; phosphate.

Figure 1

Representation of effect modifiers and mediator of phosphate toxicity on the cardiovascular system at the right. Modifiers can either increase or mitigate direct effects of phosphate on target tissues. Mediators are the consequence of phosphate exposure and inflict harm directly, once formed. CPP: Calciprotein particle. MGP: Matrix Gla Protein.

Figure 2

Calciprotein particles (CPP1, left) are spherical particles containing calcium and phosphate ions organized by fetuin-A are covered by fetuin-A, shielding the crystals from the surroundings. Secondary CPP (CPP2) are needle shaped configurations as a consequence of non-organized expanding crystallization as the consequence of either high concentrations of calcium and phosphate, relative deficiency of fetuin A, or otyher metabolic conditions that promote CPP formation, as detailed in the text. Reproduced with permission from Holt et al. 2016, Oxford University Press [20].

Figure 3

Odds ratio for cardiovascular mortality in a large Japanese cohort of patients on hemodialysis. (A) Reflects lower magnesium group, (B) intermediate magnesium group and (C) higher magnesium group. The dashed line represents the 95% confidence interval. The reference serum phosphate value is 4.5 mg/dL. Reproduced with permission from Sakaguchi et al. [53], 2014, PLoS One.

Figure 4

Uptake by vascular smooth muscle cells under varying concentration of α-klotho, and at two different concentrations of inorganic phosphate. On the Y-axis phosphate uptake is shown, on the X-axis concentrations of α-klotho. At higher concentrations α-klotho the uptake is inhibited, for both normal and high phosphate concentration in the medium. Reproduced with permission from Hu et al. [87] 2011, Am Soc Nephrol.